This contributes to the dimerization of identical or different proteins, and to attain structural conformers of the target protein modulating their functionality (reviewed in ). This structure permits the interaction of CaM with its targets adopting different conformations, and to work as a linker between different proteins and/or segments of the same polypeptide chain. The structure of CaM consists in two globular lobes located at the N- and C-termini of the protein each containing two EF-hand Ca 2+-binding sites and a flexible linker connecting both globular lobes. The best-studied EF-hand containing protein is calmodulin (CaM). Nevertheless, this did not occur in all cases, because events of convergent evolution took place as well. By this mechanism, a predicted ancient gene encoding a single EF-hand-containing protein can be seen as a precursor yielding a plethora of different proteins working as Ca 2+-binding sensors and buffers.
The phylogeny of these proteins shows an evolutionary history, in which gene duplication played a fundamental role. It is formed by a loop of 12 amino acids rich in acidic residues, which coordinates Ca 2+, and links the two α-helical segments E and F in a perpendicular way. The name of this motif is derived from the Ca 2+-binding sites of parvalbumin, where it was first identified. The transduction of the Ca 2+ signal is mostly achieved by a great variety of Ca 2+-binding proteins containing helix–loop–helix EF-hand motifs. The calcium ion plays a fundamental signaling role in all eukaryotic organisms. The existence of proteins containing CaM-LDs or CLBSs substantially adds to the enormous versatility and complexity of Ca 2+/CaM signaling. CLBS are important regulatory motifs, acting either by keeping these CaM-binding proteins inactive in the absence of CaM, enhancing the stability of protein complexes and/or facilitating their dimerization via CBS/CLBS interaction. In addition, this review also covers CaM-binding proteins, in which their CaM-binding site (CBS), in the absence of CaM, is proposed to interact with other segments of the same protein denoted CaM-like binding site (CLBS). Importantly, this arrangement allows to this group of proteins direct regulation independent of other Ca 2+-sensitive sensor/transducer proteins, such as CaM. These segments are denoted CaM-like domains (CaM-LDs) and play a regulatory role, making these CaM-like proteins sensitive to Ca 2+ transients within the cell, and hence are able to transduce the Ca 2+ signal leading to specific cellular responses. In this review, we will discuss proteins, that in addition to their catalytic, transport, structure, localization or adaptor functions, also have segments resembling the helix-loop-helix EF-hand motifs found in Ca 2+-binding proteins, such as calmodulin (CaM). The combinatorial arrangement of different functional and/or structural domains within a single polypeptide chain yields a wide variety of activities and regulatory properties to the modular proteins.
The appearance of modular proteins is a widespread phenomenon during the evolution of proteins.
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